The present invention relates generally to mammalian cytokines, and particularly to cloning and expression of biologically active mammalian homologues of human IL-1.beta., e,g., bovine interleukin-1.sym.. Interleukin-1 (IL-1) is the designation given to a family of polypeptides, released by macrophages and certain other cell types in response to immunogenic and traumatic stimulation, which have a primary role in initiating host response to injury and infection. These cytokines have been associated with a complex spectrum of biological activities. IL-1 is a primary immunostimulatory signal capable of inducing thymocyte proliferation via induction of interleukin-2 release, and of stimulating proliferation and maturation of B lymphocytes. In addition, IL-1 has been linked with prostaglandin production and induction of fever, and with promotion of wound healing. Reviews of the literature relating to IL-1 include Oppenheim et al., Immunol. Today 7: 45 (1986), and Durum el al., Ann. Rev. Immunol. 3: 263 (1985).
Human IL-1 activity resides in two distantly related proteins, which have been designated IL-1.alpha. and IL-1.beta. (March et al., Nature 315: 641 (1985)). Both molecules are normally synthesized as larger precursors having molecular weights of about 30,000 daltons, which are subsequently processed by proteolytic cleavage to yield mature forms having molecular weights of approximately 17,500 daltons. While the precursor of human IL-1.alpha. exhibits IL-1 biological activity, the precursor of human IL-1.beta. is biologically inactive, and must be cleaved to provide a mature version having IL-1 activity.
Recently, cDNAs coding for both human IL-1 species have been cloned and expressed in microorganisms, which has enabled production of sufficient quantities of IL-1.alpha. and IL-1.beta. for preclinical research and potential therapeutic use.
In view of potential clinical utility as a vaccine adjuvant and component of wound-healing compositions, there is interest in employing bovine IL-1 proteins in veterinary medicine. Therapeutic compositions comprising biologically active quantities of bovine IL-1 proteins or active homologues could be employed to potentiate antibody production in response to vaccine antigens, and also to promote rapid epidermal wound-healing. An unexpected result of this invention is the observation that the specific activity of purified recombinant bovine IL-1.beta. in stimulating bovine thymocyte proliferation is from three to four orders of magnitude greater than the specific activity of recombinant human IL-1.beta..